在获得性 PARP 抑制剂耐药同源重组缺陷型卵巢癌中联合 ATR（ceralasertib）和 PARP（olaparib）抑制剂（CAPRI）试验。
Combination ATR (ceralasertib) and PARP (olaparib) Inhibitor (CAPRI) Trial in Acquired PARP Inhibitor-Resistant Homologous Recombination-Deficient Ovarian Cancer.
机构信息
Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
出版信息
Clin Cancer Res. 2023 Aug 1;29(15):2800-2807. doi: 10.1158/1078-0432.CCR-22-2444.
PURPOSE
Addition of ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) to PARP inhibitors (PARPi) overcomes PARPi resistance in high-grade serous ovarian cancer (HGSOC) cell and mouse models. We present the results of an investigator-initiated study of combination PARPi (olaparib) and ATRi (ceralasertib) in patients with acquired PARPi-resistant HGSOC.
PATIENTS AND METHODS
Eligible patients had recurrent, platinum-sensitive BRCA1/2 mutated or homologous recombination (HR)-deficient (HRD) HGSOC and clinically benefited from PARPi (response by imaging/CA-125 or duration of maintenance therapy; > 12 months first-line or > 6 months ≥ second-line) before progression. No intervening chemotherapy was permitted. Patients received olaparib 300 mg twice daily and ceralasertib 160 mg daily on days 1 to 7 of a 28-day cycle. Primary objectives were safety and objective response rate (ORR).
RESULTS
Thirteen patients enrolled were evaluable for safety and 12 for efficacy; 62% (n = 8) had germline BRCA1/2 mutations, 23% (n = 3) somatic BRCA1/2 mutations, and 15% (n = 2) tumors with positive HRD assay. Prior PARPi indication was treatment for recurrence (54%, n = 7), second-line maintenance (38%, n = 5) and first-line treatment with carboplatin/paclitaxel (8%, n = 1). There were 6 partial responses yielding an ORR of 50% (95% confidence interval, 0.15-0.72). Median treatment duration was 8 cycles (range 4-23+). Grade (G) 3/4 toxicities were 38% (n = 5); 15% (n = 2) G3 anemia, 23% (n = 3) G3 thrombocytopenia, 8% (n = 1) G4 neutropenia. Four patients required dose reductions. No patient discontinued treatment due to toxicity.
CONCLUSIONS
Combination olaparib and ceralasertib is tolerable and shows activity in HR-deficient platinum-sensitive recurrent HGSOC that benefited and then progressed with PARPi as the penultimate regimen. These data suggest that ceralasertib resensitizes PARPi-resistant HGSOCs to olaparib, warranting further investigation.
目的
在高级别浆液性卵巢癌（HGSOC）细胞和小鼠模型中，添加共济失调毛细血管扩张症和 Rad3 相关激酶抑制剂（ATRi）到聚腺苷二磷酸核糖聚合酶抑制剂（PARPi）中，克服了 PARPi 耐药性。我们展示了一项由研究者发起的关于 PARPi（奥拉帕利）和 ATRi（塞拉西贝特）联合治疗获得性 PARPi 耐药 HGSOC 患者的研究结果。
方法
符合条件的患者为复发性、铂类敏感的 BRCA1/2 突变或同源重组（HR）缺陷（HRD）HGSOC，在进展前曾接受过 PARPi（通过影像学/CA-125 或维持治疗的持续时间进行评估；一线治疗 > 12 个月或二线治疗 > 6 个月）获益。不允许在治疗期间进行化疗。患者接受奥拉帕利 300mg 每日两次和塞拉西贝特 160mg 每日一次，连续 28 天为一个周期，在第 1 天至第 7 天用药。主要目标是安全性和客观缓解率（ORR）。
结果
13 名入组患者可评估安全性，12 名患者可评估疗效；62%（n=8）有胚系 BRCA1/2 突变，23%（n=3）有体细胞 BRCA1/2 突变，15%（n=2）肿瘤 HRD 检测阳性。先前的 PARPi 适应证为复发治疗（54%，n=7）、二线维持治疗（38%，n=5）和一线卡铂/紫杉醇治疗（8%，n=1）。有 6 名患者出现部分缓解，缓解率为 50%（95%置信区间，0.15-0.72）。中位治疗持续时间为 8 个周期（范围 4-23+）。38%（n=5）出现 3/4 级毒性；15%（n=2）为 3 级贫血，23%（n=3）为 3 级血小板减少症，8%（n=1）为 4 级中性粒细胞减少症。有 4 名患者需要减少剂量。没有患者因毒性而停止治疗。
结论
奥拉帕利联合塞拉西贝特耐受良好，并在 HR 缺陷性铂类敏感复发性 HGSOC 中显示出活性，这些患者曾接受 PARPi 作为倒数第二线治疗获益，随后进展。这些数据表明，塞拉西贝特使 PARPi 耐药的 HGSOC 对奥拉帕利重新敏感，值得进一步研究。
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